The Cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-Methylated undecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic (in particular anti-protozoal, e.g. anti-malarial) activity. The first of the Cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trademark SANDIMMUN.RTM. or SANDIMMUNE.RTM..
Cyclosporin is a highly lipophilic drug. Therefore, cyclosporin is sparingly soluble in water, but dissolves readily in organic solvents, such as methanol, ethanol, chloroform and the like. Due to its limited solubility in water, the bioavailability of orally administered cyclosporin is extremely low. Poor bioavailability may lead to ineffective therapy, the need for higher dosing and/or undesirable side effects. Therefore, it is very difficult tc provide an effective therapeutic concentration of the drug in the body when administered orally or by routes requiring transmembrane absorption. Cyclosporin can only be formulated into a preparation for oral administration only with great difficulty. Accordingly, numerous studies have been extensively conducted to find a cyclosporin preparation effective for oral administration, that is, a preparation which provides both uniform dosage and bioavailability of the active component.
In the prior art preparations of cyclosporin suitable for oral administration, sparingly water-soluble cyclosporin has been usually formulated by combining cyclosporin with a surfactant, an oil and a co-surfactant. For example, U.S. Pat. No. 4,388,307 discloses a liquid formulation of cyclosporin that includes at least one of the following components: (a) a transesterification product of a natural or hydrogenated vegetable oil and a polyalkylene polyol; (b) a saturated fatty acid triglyceride; or (c) a mono- or diglyceride. Component (a) is formed by the transesterification of a triglyceride, e.g., a triglyceride from a vegetable oil, with polyethylene glycol. Component (b) may be obtained by esterifying a triglyceride with saturated fatty acid while component (c) is a mono- or di-glyceride, or a mono- or di-fatty acid glyceride. It is preferred that ethanol be further used as a solubulizing agent. However, since this liquid formulation is administered as an aqueous solution, it is both inconvenient and difficult to administer in an uniform dosage.
In order to mitigate the inconvenience of diluting a cyclosporin liquid composition with water prior to oral administration, the liquid composition was formulated into a soft capsule preparation, which is now commercially available as SANDIMMUN.RTM.. In this preparation, the cyclosporin soft capsule contains a large amount of ethanol as a cosurfactant in order to solubilize the cyclosporin. However, since ethanol permeates the gelatin shell of the capsule and is volatile even at normal temperatures, the constitutional ratio of the contents of the soft capsules may greatly vary during storage. The resulting reduced ethanol content may in turn result in crystallization of the cyclosporin and thus results in a significant variation in the bioavailability of cyclosporin. The variation in cyclosporin concentration in this formulation makes it quite difficult to determine the dosage needed to provide a desired therapeutic effect.
Belgian Patent No. 895,724, which relates to the use of Ciclosporin in the treatment of multiple sclerosis, also describes two oral formulations suitable for the administration of this particular compound. Both of these are based on the commercial Ciclosporin (SANDIMMUN.RTM.) drink-solution, with adaption to suit the particular cyclosporin active ingredient. The first comprises 5-10% Ciclosporin, 10-12% ethanol, 30-40% MAISINE.RTM., about 4% CREMOPHORE.RTM. and 51-30% LABRAFIL.RTM.. This corresponds to the composition of the liquid oral formulation of SANDIMMUN.RTM., but with the replacement of the natural vegetable oil component with MAISINE.RTM. and the introduction of a minor percentage of the tenside CREMOPHORE.RTM.. MAISINE.RTM. is a trans-esterification product of corn oil with glycerol. The ratio of Cyclosporin: tenside in the disclosed composition is 1:0.4-0.8. Inasmuch as ethanol is a key component of the formulation, it does not make any suggestion to replace ethanol as co-solvent/cosurfactant.
An Australian Patent Application discloses the use of tensides belonging to the group comprising polyethoxylated castor oils, polyethoxylated hydrogenated castor oils and polyethoxylated fatty acids derived from castor oil or hydrogenated castor oil, such as CREMOPHOR.RTM., MYRJ.RTM., and NIKKOL HCO-60.RTM., as solubilizers for the incorporation of sparingly soluble pharmaceutical agents into controlled release systems such as hydrophillic gel systems. It alleges that ciclosporine is an example of a drug that is difficult to solubilize, although it gives no specific embodiment containing this drug.
U.S. Pat. No. 5,342,625 discloses cyclosporin in association with a hydrophilic phase, lipophilic phase and a surfactant. The hydrophilic phase comprises 1,2-propylene glycol or R.sub.1 --[O--CH.sub.2).sub.x ]--OR.sub.2, where R.sub.1 and R.sub.2 are independently alkyl containing 1-5 carbon atoms or tetrahydrofuryl and x is 1-6 and R.sub.2 is hydrogen. Such ethers are commercially available under the trade name of Transcutol and Glycofurol; in addition, it may contain C.sub.1-5 alkanols, such as ethanols.
However, the use of ethanol as well as other solvents such as 1,2,propylene glycol or liquid polyethylene glycols in these sorts of systems creates several problems. Since ethanol permeates the gelatin shell of the capsule and is volatile, even at room temperature, the constitutional ratio of the contents of the soft capsules may greatly vary during storage. The resulting reduced ethanol content may in turn result in crystallization of the cyclosporin, and this results in a significant variation in the bioavailability of cyclosporin when administered to an animal. The variation in cyclosporin concentrate in these types of formulations makes it quite difficult to determine the dosage needed to provide a desired therapeutic effect. Moreover, when solvents such as ethanol, 1,2-propylene glycol and liquid polyethylene glycols are utilized in gelatin capsules, these solvents have a tendency to absorb moisture, thereby rendering brittle the shell walls, especially those in hard gelatin capsules, and thereby resulting in leakage of the contents of the capsules during storage or shipment. Moreover, one of the biggest drawbacks using hydrophilic components, as in U.S. Pat. No. 5,342,625, has beer the potential of reprecipitation of the drug from the formulation when it comes into contact with aqueous systems, such as in the stomach or intestine after ingestion by the mammal.
Moreover, the complexity of the ternary formulations as in U.S. Pat. No. 5,342,625 makes them costly and difficult to manufacture. Moreover, U.S. Pat. No. 5,342,625 suggests the use of solvents such as Glycofurol and Transcutol which are restricted for pharmaceutical use by several regulatory agencies worldwide, including the FDA, because they are not considered "Generally Recognized As Safe" (GRAS) for oral use. Further, with hydrophilic solvents there is always an added risk of precipitation of the cyclosporin on exposure to gastrointestinal fluids in vivo, thereby further affecting bioavailability.
U.S. Pat. No. 4,970,076 discloses use of GLA (gamma linoleic acid) and DGLA (dihomogammalinolenic acid) and their derivatives as active components in pharmaceutical compositions to counter the adverse side effects of cyclosporin, such as nephrotoxicity and renal side effects. It, however, does not teach or even recognize the use of the lipophilic materials for enhancing the solubility, bioavailability, emulsion or microemulsion capability.
A couple of very recent patents, U.S. Pat. Nos. 5,759,997 and 5,858,401, disclose the use of a mixture of mono-, di- and triglycerides and a monoglyceride respectively, as a carrier for cyclosporin formulations. The formulations therein do not contain a hydrophilic component, such as alcohol, propylene glycol, and the like. However, the formulation therein has several drawbacks. For example, some of the problems encountered with these formulations includes the limited solubility of cyclosporin therein. As a result, the size of the capsules required to accommodate the required dose, e.g., 100 mg, is very large. This causes a major inconvenience to the patient, resulting in a larger pill or capsule, thereby making it more difficult for the patient to swallow the same. This in turn, tends to minimize compliance by the patients who have to take multiple capsules per day.
Moreover, in addition, the stability of this formulation, especially those having a high monoglyceride content when used in hard gelatin capsules, is extremely limited; monoglycerides have a tendency to make the gelatin shells brittle, causing leakage of the contents of such capsules.
It is apparent that there is a need to prepare formulations of cyclosporins which minimize the number of components that are to be administered to the patient. There is also a need to prepare formulations of cyclosporin having greater solubility which provide higher drug loading, use components considered as GRAS and offer advantageous formulation stabilities, desirable pharmokinetics and bioavailability and/or ease of manufacture.
The present inventor has surprisingly found such a system which overcomes the problems of limited solubility and resulting bioavailability associated with cyclosporin. Unlike the formulation used heretofore, it has been found that the use of a carrier system comprising a non-ionic surfactant in conjunction with a cyclosporin solubilizing agent consisting essentially of C.sub.6 -C.sub.22 fatty acids overcomes the problems described herein.
No one heretofore utilized the carrier system of the present invention or realized the advantages, as described hereinbelow, of this carrier system in combination with cyclosporin.
It has been found that by employing the above defined carrier system, it is possible to obtain cyclosporin formulations which do not require any solvent or co-solvent such as alcohol, propylene glycol, polyethylene glycol, and the like, in amounts effective to solubilize the drug. Therefore, problems associated with these solvents, as mentioned hereinabove, are eliminated by the present invention. Thus, the compositions of the present invention are more stable and provide higher drug-loading than those compositions containing cyclosporin associated with alcohols, in which the alcohols are utilized and present in amounts effective for dissolving cyclosporin or acting as surfactants or co-surfactants.
Due to the greater solubility of cyclosporin in the C.sub.1 -C.sub.22 fatty acids, the present formulation has a concomitant advantage: there is an increase in drug loading. For example, the size of the capsule for the delivery of unit doses containing cyclosporin is reduced in the present invention, providing greater patient acceptance and compliance. Moreover, if the oral dosage form is a capsule, there is an excellent compatibility of the C.sub.6 -C.sub.22 fatty acids with hard or soft shell gelatin capsules, thereby preventing brittleness and leakage of the formulation during storage. Furthermore, the present pharmaceutical composition is a preconcentrate which forms an emulsion, preferably forms a fine emulsion and most preferably forms a microemulsion upon exposure to aqueous fluid (e.g., water, for instance the g.i. tract) which provides higher and uniform bioavailability. This characteristic further helps reduce the intra- and inter-subject variability associated with the absorption of the lipophilic active component, as well as minimize the effect of food on the absorption and bioavailability of cyclosporin in mammals.